Polyphosphate (polyP) is a highly anionic, linear polymer of inorganic phosphate that accumulates in many infectious microorganisms (1) and is secreted by activated human platelets (2). The platelet polyP acts as a procoagulant stimulus at a number of points in the coagulation cascade including: accelerating factor V activation, antagonizing the anticoagulant function of tissue factor pathway inhibitor (TFPI), making clots more resistant to fibrinolysis, and enhancing factor XI activation by thrombin (3). Although, current understanding of the mechanisms behind polyP's acceleration of clotting and which mechanisms are most relevant in vivo, are incomplete. The role of platelet polyP in hemostasis and thrombosis suggests that it may contribute more heavily to thrombosis. Additionally, its role as an accelerant rather than a key enzyme in the final common pathway of the coagulation cascade (unlike, for example, thrombin or factor Xa), suggests that platelet polyP is an attractive therapeutic target for novel antithrombotics with potentially decreased bleeding risk compared to conventional therapies (4). Current antithrombotic drugs used in a clinical setting include, heparin, which has significant toxicity in cell culture (5) and carries risk of major bleeding events and heparin-induced thrombocytopenia, even in heparin-naïve patients (6, 7).
Cationic polymers make attractive candidates for high-affinity polyP inhibitors, and such polymers, including polyethylenimine (PEI) and polyamidoamine (PAMAM) dendrimers, have proven effective in attenuating thrombosis in proof-of-principle studies that identified polyP as a therapeutic target (8, 9). Both of these types of polymers are positively charged due the presence of multiple primary amines, which allows them to bind to and inhibit polyP, but this property can also promote binding to proteins and cell surfaces and thus lead to cellular toxicity, platelet activation, and coagulopathy mediated by fibrinogen aggregation (10, 11). This severely limits the real-world usefulness of these previously identified polyP inhibitors.